Evolution of strategies to prepare synthetic mimics of carboxylate-bridged diiron protein active sites

We present a comprehensive review of research conducted in our laboratory in pursuit of the long-term goal of reproducing the structures and reactivity of carboxylate-bridged diiron centers used in biology to activate dioxygen for the conversion of hydrocarbons to alcohols and related products. This article describes the evolution of strategies devised to achieve these goals and illustrates the challenges in getting there. Particular emphasis is placed on controlling the geometry and coordination environment of the diiron core, preventing formation of polynuclear iron clusters, maintaining the structural integrity of model complexes during reactions with dioxygen, and tuning the ligand framework to stabilize desired oxygenated diiron species. Studies of the various model systems have improved our understanding of the electronic and physical characteristics of carboxylate-bridged diiron units and their reactivity toward molecular oxygen and organic moieties. The principles and lessons that have emerged from these investigations will guide future efforts to develop more sophisticated diiron protein model complexes.National Institute of General Medical Sciences (U.S.

Developing functional protein mimics through ligand design and understanding dioxygen activation

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2011.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Vita. Cataloged from student submitted PDF version of thesis.Includes bibliographical references.Chapter 1 A comprehensive review of diiron modeling in the Lippard group over the past thirty years is presented. This account describes the different strategies employed to prepare biomimetic complexes of non-heme diiron protein active sites, highlighting the accomplishments of the past as well as the challenges for the future. Studies of various model systems have led to a more profound understanding of the fundamental properties of carboxylate-bridged diiron units and their reactivity toward molecular oxygen and organic substrates. The key principles and lessons that have emerged from these studies have been an inspiration for the original work presented in this thesis. Chapter 2 A series of phenoxylpyridyl and phenoxylimine ligands, H2LR,R' (compounds derived from bis(phenoxylpyridyl)diethynylbenzene, where R = H, Me, or t-Bu, and R' = H, or Ph) and H2BIPSMe,Ph (bis((phenylphenoxyl)iminephenyl)sulfone) were synthesized as platforms for non-heme diiron(II) protein (III) core and molecular oxygen as the source of the bridging oxo group. The [LMe,Ph]2- ligand is robust toward oxidative decomposition and does not display any reversible redox activity. Chapter 3 A dinucleating macrocycle, H2PIM, containing phenoxylimine metal-binding units has been prepared. Reaction of H2PIM with [Fe2(Mes)4] (Mes = 2,4,6-trimethylphenyl) and sterically hindered carboxylic acids, Ph3CCO2H or ArTolCO2H (2,6-bis(p-tolyl)benzoic acid), afforded complexes [Fe2(PIM)(Ph3CCO2)2] (1) and [Fe2(PIM)(ArTolCO2)2] (2), respectively. X-ray diffraction studies revealed that these diiron(II) complexes closely mimic the active site structures of the hydroxylase components of bacterial multi-component monooxygenases (BMMs), particularly the syn disposition of the nitrogen donor atoms and the bridging [mu]--n1n2 and [mu]-n1n1 modes of the carboxylate ligands at the diiron(II) centers. Cyclic voltammograms of 1 and 2 displayed quasi-reversible redox couples at +16 and +108 mV vs. ferrocene/ferrocenium, respectively, assigned to metal-centered oxidations. Treatment of 2 with silver perchlorate afforded a silver(I)/diiron(III) heterotrimetallic complex, [Fe2([mu]-OH)2(CIO4)2(PIM)(ArTolCO2)Ag] (3), which was structurally and spectroscopically characterized. Complexes 1 and 2 both react rapidly with dioxygen. Oxygenation of 1 afforded a ([mu]-hydroxo)diiron(III) complex [Fe2([mu]- OH)(PIM)(Ph3CCO2)3] (4), a hexa([mu]-hydroxo)tetrairon(III) complex [Fe4([mu]- OH)6(PIM)2(Ph3CCO2)2] (5), and an unidentified iron(III) species. Oxygenation of 2 exclusively formed di(carboxylato)diiron(III) products. X-ray crystallographic and 57Fe Mössbauer spectroscopic investigations indicated that 2 reacts with dioxygen to give a mixture of ([mu]- oxo)diiron(III) [Fe2([mu]-O)(PIM)(ArTolCO2)2] (6) and di([mu]-hydroxo)diiron(III) [Fe2([mu]- OH)2(PIM)(ArTolCO2)2] (7) complexes in the same crystal lattice. Compounds 6 and 7 spontaneously convert to a tetrairon(III) complex, [Fe4([mu]-OH)6(PIM)2(ArTolCO2)2] (8), when treated with excess H2O. The possible biological implications of these findings are discussed. Chapter 4 To investigate how protons may be involved in the dioxygen activation pathway of non-heme diiron enzymes, the reaction of H+ with a synthetic ([mu]-1,2-peroxo)(carboxylato)diiron(III) complex was explored. Addition of an H+ donor to [Fe2(O2)(N-EtHPTB)(PhCO2)]2+ (1.O2, where N-EtHPTB = anion of N,N,N' ,N' -tetrakis(2-benzimidazolylmethyl)-2-hydroxy-1,3-diaminopropane) resulted in protonation of the carboxylate rather than the peroxo ligand. Mössbauer and resonance Raman spectroscopic measurements indicate that the Fe2(O2) core of the protonated complex [1.O2]H+ is identical to that of 1.O2. In contrast, the benzoate ligand of [1.O2]H+ displays significantly different IR and NMR spectral features relative to those of the starting complex. The [1.O2]H+ species can be converted back to 1.O2 upon treatment with base, indicating that protonation of the carboxylate is reversible. These findings suggest that in the reaction cycle of soluble methane monooxygenases and related diiron proteins, protons may 6 induce a carboxylate shift to enable substrate access to the diiron core and/or increase the electrophilicity of the oxygenated complex. Chapter 5 To explore additional methods to interrogate the properties of diiron protein intermediates, studies of the vibrational profiles of ([mu]-1,2-peroxo)diiron(III) species were pursued using nuclear resonance vibrational spectroscopy (NRVS). Comparison of the NRVS of [Fe2(O2)(NEtHPTB)(PhCO2)]2+ (1.O2) to that of the diiron(II) starting material [Fe2(N-EtHPTB)(PhCO2)]2+ (1) revealed that the oxygenated complex displays new frequencies above 350 cm-1, which are attributed to the Fe-O-O-Fe core vibrations based on 18O2/16O2 isotopic labeling studies. The peak at 338 cm-1 has not been previously observed by resonance Raman spectroscopy. Empirical normal mode analysis provides a qualitative description of these isotopic sensitive modes. The NRVS of [Fe2([mu]-O2)(HB(iPrpz)3)2(PhCH2CO2)2] (4.O2, where HB(iPrpz)3 = tris(3,5-diisopropylpyrazoyl) hydroborate) was also measured and shows several Fe2(O2) modes between 350-500 cm-1. Appendix A Attempts to prepare a diiron(IV) complex described in the literature led to several unexpected discoveries. Reaction of tris((3,5-dimethyl-4-methoxy)pyridyl-2-methyl)amine (R3TPA) with iron(III) perchlorate decahydrate and sodium hydroxide afforded a ([mu]-oxo)([mu]-hydroxo)diiron(III) [Fe2([mu]-O)([mu]-OH)(R3TPA)2](ClO4)3 complex (1), rather than [Fe2([mu]-O)(OH)(H2O)-(R3TPA)2](ClO4)3 (B) as previously reported. The putative diiron(III) starting material B is formed only at low temperature when excess water is present. Compound 1 hydrolyzes acetonitrile to acetate under ambient conditions. The acetate-bridged diiron compound, [Fe2([mu]- O)([mu]-CH3CO2)(R3TPA)2](ClO4)3 (4A), was characterized by X-ray crystallography as well as various spectroscopic methods and elemental analysis. The identity of the acetate bridged complex was confirmed by comparing the structural and spectroscopic characteristics of 4A to those of an independently prepared sample of [Fe2([mu]-O)([mu]-CH3CO2)(R3TPA)2](ClO4)3.by Loi Hung Do.Ph.D

Characterization of a synthetic peroxodiiron(III) protein model complex by nuclear resonance vibrational spectroscopy

The vibrational spectrum of an η[superscript 1],η[superscript 1]-1,2-peroxodiiron(III) complex was measured by nuclear resonance vibrational spectroscopy and fit using an empirical force field analysis. Isotopic 18O2 labelling studies revealed a feature involving motion of the {Fe2(O2)}[superscript 4+] core that was not previously observed by resonance Raman spectroscopy.National Institute of General Medical Sciences (U.S.) (GM-032134

Application of satellite images and VNREDSAT-1 images in study on marine environment in Truong Sa region

The remote sensing images, including images of MODIS, VNREDSAT-1 and altimeter, are applied for researching marine environment with the different resolutions. On the basis of different time remote sensing images, we concentrated on the assessment of several characteristics including the SST, chlorophyll-a concentration and sea surface current at the different depths in different monsoons as well. With the large areas, we used the images of MODIS and altimeter. The detailed research area focuses on the Nam Yet island, and the images of VNREDSAT-1 are used. The analysis method of environmental parameters of SST and chlorophyll-a used the regression functions based on the single and combined bands to enhance the accuracy of the analysis result. The marine parameters collected at different depths in the latest field surveys on Truong Sa archipelago in the years of 2015 and 2018 are presented in this paper. On the basis of these parameters, we can analyse the relationships and compare the real field survey data and corresponding results interpreted from remote sensing images

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Chemical composition of the oil of Blumea lanceolaria (Roxb.) Druce from Vietnam

The essential oil of Blumea lanceolaria (Roxb.) Druce was analyzed by capillary gas chromatography and mass spectrometry. The main constituent was found to be methyl thymol (95%) which was confirmed by NMR spectrometry

Chemistry of Nitrosyliron Complexes Supported by a β-Diketiminate Ligand

Several nitrosyl complexes of Fe and Co have been prepared using the sterically hindered Ar-nacnac ligand (Ar-nacnac = anion of [(2,6-diisopropylphenyl)NC(Me)]2CH). The dinitrosyliron complexes [Fe(NO)2(Ar-nacnac)] (1) and (Bu4N)[Fe(NO)2(Ar-nacnac)] (2) react with [FeIII(TPP)Cl] (TPP = tetraphenylporphine dianion) to generate [FeII(NO)(TPP)] and the corresponding mononitrosyliron complexes. The factors governing NO transfer with dinitrosyliron complexes (DNICs) 1 and 2 are evaluated, together with the chemistry of the related mononitrosyliron complex, [Fe(NO)Br(Ar-nacnac)] (4). The synthesis and properties of the related cobalt dinitrosyl [Co(NO)2(Ar-nacnac)] (3) is also discussed for comparison to DNICs 1 and 2. The solid-state structures of several of these compounds as determined by X-ray crystallography are reported.National Science Foundation (U.S.) (grant CHE-0907905)National Institute of General Medical Sciences (U.S.) (postdoctoral fellowship, F32 GM082031-03

Carboxylate as the Protonation Site in (Peroxo)diiron(III) Model Complexes of Soluble Methane Monooxygenase and Related Diiron Proteins

Dioxygen activation by carboxylate-bridged diiron enzymes is involved in essential biological processes ranging from DNA synthesis and hydrocarbon metabolism to cell proliferation.1-3 The carboxylate-bridged diiron superfamily of proteins includes ribonucleotide reductase (RNR),4 Δ9 desaturase,5 bacterial multicomponent monooxygenases (BMMs),6,7 and most recently human deoxyhypusine hydroxylase (hDOHH).3 In all of these systems, the O2 reduction step proceeds through a (peroxo)- diiron(III) intermediate in which the resulting peroxo ligand is proposed to bridge two iron atoms in a μ-1,2 or μ-η2η2 coordination mode.8-10 Extensive studies of soluble methane monooxygenase (sMMO), a BMM family member that oxidizes methane to methanol, reveal that the generation and activation of Fe2O2 units requires protons.11,12 Given the complexity of protein environments, identifying the sites involved in such proton translocation processes and their effect on O2 activation is not a trivial undertaking.National Institute of General Medical Sciences (U.S.) (grant GM032134)National Institute of General Medical Sciences (U.S.) (grant GM74785

Composing biodiversity indicators for the conservation of mangrove ecosystem in Xuan Thuy National Park, Vietnam: Research article

Biodiversity indicators for the conservation of mangrove ecosystems of Xuan Thuy National Park were composed, taking into account the environmental, biotic, and anthropological factors, based on suggested indicators provided by the Convention on Biological Diversity. Relevant environmental, biotic, and anthropological factors, identified by bibliographic and field surveys, were ordered by Pressures, State, Benefits, and Responses categories following the guidance of the Biodiversity Indicators Partnership. Furthermore, the linked relationships among the indicators were identified for effective monitoring of biodiversity in Xuan Thuy National Park.Dựa trên các chỉ thị được gợi ý từ Công ước về Đa dạng sinh học, các chỉ thị đa dạng sinh học phục vụ công tác bảo tồn các hệ sinh thái rừng ngập mặn của Vườn Quốc gia Xuân Thủy đã được xây dựng, có tính đến các yếu tố môi trường, sinh học và con người. Các yếu tố môi trường, sinh học và con người có liên quan, được xác định bằng việc tổng hợp và đánh giá các tài liệu và các đợt điều tra ngoài thực địa, dưới trật tự các nhóm Áp lực, Tình trạng, Lợi ích và Đáp ứng theo hướng dẫn của Đối tác chỉ thị đa dạng sinh học. Hơn thế nữa, các mối quan hệ liên kết giữa các chỉ thị đã được xác định nhằm quan trắc hiệu quả đa dạng sinh học ở Vườn Quốc gia Xuân Thủy